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Human Molecular Genetics Advance Access originally published online on March 11, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 9 935-944
DOI: 10.1093/hmg/ddh109
Human Molecular Genetics, Vol. 13, No. 9 © Oxford University Press 2004; all rights reserved

Mitochondrial transcription factor A regulates mtDNA copy number in mammals

Mats I. Ekstrand1,2, Maria Falkenberg1, Anja Rantanen1,2, Chan Bae Park1,2, Martina Gaspari1,2, Kjell Hultenby3, Pierre Rustin4, Claes M. Gustafsson1 and Nils-Göran Larsson1,2,*

1Department of Medical Nutrition and 2Department of Biosciences, 3Clinical Research Center, Karolinska Instititutet, Novum, S-141 86 Stockholm, Sweden and 4Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U393, Hôpital des Enfants-Malades, Paris, France

Received January 28, 2004; Accepted March 2, 2004

Mitochondrial DNA (mtDNA) copy number regulation is altered in several human mtDNA-mutation diseases and it is also important in a variety of normal physiological processes. Mitochondrial transcription factor A (TFAM) is essential for human mtDNA transcription and we demonstrate here that it is also a key regulator of mtDNA copy number. We initially performed in vitro transcription studies and determined that the human TFAM protein is a poor activator of mouse mtDNA transcription, despite its high capacity for unspecific DNA binding. Next, we generated P1 artificial chromosome (PAC) transgenic mice ubiquitously expressing human TFAM. The introduced human TFAM gene was regulated in a similar fashion as the endogenous mouse Tfam gene and expression of the human TFAM protein in the mouse did not result in down-regulation of the endogenous expression. The PAC-TFAM mice thus had a net overexpression of TFAM protein and this resulted in a general increase of mtDNA copy number. We used a combination of mice with TFAM overexpression and TFAM knockout and demonstrated that mtDNA copy number is directly proportional to the total TFAM protein levels also in mouse embryos. Interestingly, the expression of human TFAM in the mouse results in up-regulation of mtDNA copy number without increasing respiratory chain capacity or mitochondrial mass. It is thus possible to experimentally dissociate mtDNA copy number regulation from mtDNA expression and mitochondrial biogenesis in mammals in vivo. In conclusion, our results provide genetic evidence for a novel role for TFAM in direct regulation of mtDNA copy number in mammals.

* To whom correspondence should be addressed. Tel: +46 858583724; Fax: +46 87795383; Email: nils-goran.larsson{at}mednut.ki.se


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